Monday 25 July 2011
Encouraging results of UK Duchenne exon skipping clinical trial published
The full results of the UK exon skipping trial for Duchenne muscular dystrophy have been published showing that dystrophin - the protein missing in boys with Duchenne - was produced with no significant side effects. The trial involved delivering a 'molecular patch' (AVI-4658) to the whole body by injection into the bloodstream. Three of the trial participants had a strong response to the 12-week treatment - one had almost a fifth of the amount of dystrophin normally found in healthy muscle. There were also indications that the new dystrophin was working correctly in muscle. However, the response to the treatment was very variable from patient to patient.
The drug tested in this clinical trial was developed by scientists in the MDEX consortium and they conducted this trial with funding from the UK Medical Research Council (MRC) and the pharmaceutical industry. The Muscular Dystrophy Campaign has invested more than one million pounds into the development of this therapy over the past 20 years and was instrumental in setting up the MDEX consortium. We continue to represent the patient's voice as one of the three charities on the MDEX scientific advisory board.
- What happened during the trial?
- What were the results of the trial?
- How are these results different to those released in June 2010?
- What does this mean for patients and what are the next steps?
- Background information
- Further information and links
The molecular patch tested in this trial is designed to skip exon 51 of the dystrophin gene which could potentially be used to treat 13 percent of boys with Duchenne muscular dystrophy. The main aim of this clinical trial was to assess the safety of body-wide treatment with AVI-4658. A previous trial involved injecting AVI-4658 into just one muscle in the foot.
The 19 participants in the trial aged between five and 15 were treated with the 'molecular patch' at either Great Ormond Street Hospital in London or the Royal Victoria Infirmary in Newcastle. The first patient started treatment in February 2009. They had weekly intravenous infusions (needle into the vein) for 12 weeks at one of six different doses (0.5, 1.0, 2.0, 4.0, 10 or 20 mg per kg of body weight). They started treatment with the lowest dose and if this appeared safe, they moved up to the next highest dose. Muscle biopsies were taken from the biceps before and after treatment to look for increased levels of dystrophin - the protein missing in boys with Duchenne muscular dystrophy. Blood and urine samples were collected and heart, muscle and lung function monitored.
All of the participants' biopsies had evidence of skipping of exon 51 showing that the drug was active. In six of the eight participants in the two highest dose groups the researchers were able to detect new dystrophin protein in the muscle fibres. In the low dose groups there was no detectible increase in dystrophin protein, with the exception of one boy (2.0 mg per kg group).
Three participants had a strong response with 21, 15 and 55 percent of the muscle fibres containing at least some dystrophin protein after treatment with AVI-4658. These three participants were from three different dose groups; 2.0, 10 and 20 mg per kg respectively. The total amount of dystrophin present was also measured before and after treatment. The strongest responder had almost a fifth of the amount of dystrophin normally found in healthy muscle.
However, the response to the treatment was variable from patient to patient. For example, one boy in the highest dose group only had five percent of his muscle fibres containing a small amount of dystrophin after treatment.
The authors of the paper commented that they have not yet found an explanation for why some boys responded better than others. They speculated that one explanation could be that only a tiny sample of muscle was examined so they may have been unlucky in some cases and chosen an area where there was little dystrophin produced but other areas of muscle may have had more. Other monitoring techniques such as MRI scans may be able to give a more accurate picture of the success of a treatment throughout the whole body in future trials. Read more about MRI.
To confirm that the new dystrophin was working correctly in muscle, they looked at its interaction with other proteins in the muscle. In the strong responders there were indications that the dystrophin was interacting as it should in muscle which is a good sign that the newly made dystrophin will be able to help protect muscle cells from damage.
After treatment with AVI-4658 less inflammation was seen in the majority of patients in the high dose groups. In Duchenne muscular dystrophy inflammation can contribute to muscle degeneration, so reduced inflammation is encouraging.
There were no significant changes in lung or muscle function throughout the study. Creatine kinase levels also stayed the same, as did the distance walked in six minutes. This was not surprising given the short duration of the study.
Importantly the molecular patch appeared to be safe and well tolerated by all participants and no immune response to dystrophin was detected.
In June 2010 the company involved in this clinical trial - AVI Biopharma - released to the press some of the key results of the trial relating to the amount of dystrophin produced. However, this new publication contains the full detailed results of the trial and has been reviewed and accepted by a peer reviewed medical journal - The Lancet. Peer review means that other scientific experts in the field have checked the validity and significance of the results.
It is very encouraging that in this trial the boys receiving the higher doses of AVI-4658 produced new dystrophin that appeared to be working correctly in the muscle. The levels of dystrophin produced by some of the boys are thought to be high enough to have a positive impact on the prevention of muscle degeneration in Duchenne muscular dystrophy.
However, the response to the treatment was very variable from patient to patient. A new clinical trial due to start towards the end of 2011 will test a higher dose of AVI-4658 in order to try to achieve a more consistent response amongst the boys treated. Testing higher doses is possible because even at the highest dose in this trial there were no significant side effects. However, caution is required because the treatment would be lifelong - vigilant monitoring for side effects will need to continue to identify any dangerous side effects that develop after longer term treatment.
We still don't know how effective this potential new treatment will be at slowing the progression of Duchenne muscular dystrophy; larger, longer trials are needed to determine this. These trials are now being planned.
Dr Marita Pohlschmidt, Director of Research at the Muscular Dystrophy Campaign said:
We have fought to find a treatment for this devastating condition for the past 50 years. Today we can say with real confidence that we're going to win that battle. Parents of these boys can have real hope for the future.
Professor Francesco Muntoni, Chair of the MDEX consortium said:
These are very exciting results that prove the case for an even more detailed look at this genetic therapy. I've worked with patients with Duchenne muscular dystrophy for many years and this is the first time we can say with confidence that we've made a significant breakthrough towards finding a targeted treatment.
Importantly, the study drug was extremely well tolerated, with no appreciable side effect detected during the study period in any of the boys. If our strategy shows continued success, this therapy could substantially reduce muscle damage in boys with Duchenne, improve their quality of life, their mobility and the way their condition is managed as they get older.
So far scientists have shown this technique to be effective in a dog and a mouse model of Duchenne muscular dystrophy. These animal models have been essential for the development of the therapy prior to testing in humans.
Exon skipping is a personalised medicine - the molecular patch needs to be tailored to the specific mutation in the dystrophin gene. Mutations can occur anywhere along the gene but some areas - such as around exon 51 - more commonly have mutations than others. Although the molecular patch tested in this clinical trial can only treat 13 percent of boys with Duchenne, exon skipping has the potential to treat up to 80% of boys with Duchenne muscular dystrophy once more molecular patches are developed. More patches are already in the pipeline.
Skipping of exon 51 is also being trialled by the company Prosensa in partnership with GSK using a chemical formulation of molecular patch that differs slightly from that used by AVI Biopharma. Read about the recent Prosensa clinical trial results. A phase 3 clinical trial is now under way to test this molecular patch in more boys for a longer period of time. Please see "Further information and links" below for details of the ongoing clinical trials.
Find out how exon skipping works.
Read about the research we're funding to develop the next generation of exon skipping drugs.
Comment or ask questions about this research in the TalkMD forum.
Summaries of ongoing exon skipping clinical trials:
- Phase 3 study of the effect of a drug to skip exon 51 (GSK2402968)
- Testing the safety of a drug to skip exon 51 (GSK2402968) in boys who are unable to walk
- Investigating two doses of a drug to skip exon 51 (GSK2402968)
- Phase 1/2 study investigating the skipping of exon 44
More information about Duchenne muscular dystrophy.
Read about this news in the media:
Watch a video of Prof. Muntoni talking about this research.
The full original paper was published in The Lancet and is available for free through our partnership with Patient Inform. The article is written in technical language with no summary in layman's terms. Click here to access the full article (free registration with The Lancet is required):
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